Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite an initial 80% response rate, the 5-year survival rate is only 15% as most patients develop recurrence. In the recurrent setting, co-presentation with micrometastasis and chemoresistance limits the value of available treatment options. Therefore, to improve survival it is critical to understand the mechanisms that promote recurrence and metastasis and to develop novel approaches to prevent it. To achieve this, elucidation of the cellular origin and regulatory processes governing metastasis is a requisite. We propose that in EOC, metastatic potential is limited to a subfraction of cancer cells with inherent plasticity, stemness, and a mesenchymal/migratory phenotype: the mesenchymal cancer stem cells (mCSCs). We show evidence that mCSCs originate from EOC stem cells and that its generation is strongly driven by the TGF/Twist1 axis independent of the classical TGF/Smad pathway. Therefore, our central hypothesis is that specific targeting and controlled release of TGF? inhibitors in the tumor microenvironment will potently block the TGF/Twist1 pathway to prevent the formation of mCSCs and decrease metastatic tumor burden. We have developed a nanoscale liposomal polymeric gel (nLGs) platform coated with the RGD peptide (Arg-Gly-Asp), which targets the cellular adhesion molecule, av3 integrins that are highly expressed in tumor-associated neovasculature. Importantly, in addition to conferring specificity, the proposed nLG delivery platform also provides a synergistic two-prong approach for TGF? inhibition. Our specific aims are: Aim 1. To determine the role of TGF /PKC pathway in Twist1 stabilization and generation of mesenchymal/migratory ovarian cancer stem cells; Aim 2. Characterization of tumor neovasculature-targeted delivery system for simultaneous inhibition of TGF processing and secretion for prevention of metastasis; Aim 3. To determine the efficacy of av3-directed nanoparticle with encapsulated TGF inhibitor in an EOC in vivo model. Upon completion of these studies, we will have a better understanding of the initiation and establishment of metastatic disease in EOC and we will provide a novel therapeutic approach to decrease metastatic tumor burden using a safe and promising particulate delivery platform. With this new perspective, we will be able to create a better plan of management to decrease metastatic load and improve patient survival in this lethal gynecologic malignancy.